Evaluated articles

eLife assessment

This study identifies the molecular determinants of LRMP co-regulation of HCN 4 activity. The evidence supporting the conclusions, which is compelling, is backed by rigorous electrophysiological and spectroscopic analysis. The work is important because it greatly enhances our understanding of the mechanisms of HCN channel regulation in a tissue-specific manner and highlights a functional role for more disordered regions that have yet to be structurally resolved.

eLife Assessment

This important study provides proof of principle that C. elegans models can be used to accelerate the discovery of candidate treatments for human Mendelian diseases by detailed high-throughput phenotyping of strains harboring mutations in orthologs of human disease genes. The data are compelling and support an approach that enables the potential rapid repurposing of FDA-approved drugs to treat rare diseases for which there are currently no effective treatments. The work will be of interest to all geneticists.

eLife assessment

This study presents fundamental findings on the evolution of extremely elongated mandibular symphysis and tusks in longirostrine gomphotheres from the Early and Middle Miocene of northern China. The integration of multiple methods provides compelling results in the eco-morphology, behavioral ecology, and co-evolutionary biology of these taxa. In doing so, the authors elucidate the diversification of fossil proboscideans and their likely evolutionary responses to late Cenozoic global climatic changes.

eLife assessment

This valuable manuscript reports on the relationship between GTP hydrolysis parameters and kinase activity of LRRK2, which is associated with Parkinson's disease. The authors provide a detailed accounting of the catalytic efficiency of the ROC GTPase domain of pathogenic variants of LRRK2, in comparison with the wild-type enzyme. The authors propose that phosphorylation of T1343 inhibits kinase activity and influences monomer-dimer transitions, but the experimental evidence is currently incomplete.

eLife assessment

This is a theoretical analysis that gives compelling evidence that length control of bundles of actin filaments undergoing assembly and disassembly emerges even in the absence of a length control mechanism at the individual filament level. Furthermore, the length distribution should exhibit a variance that grows quadratically with the average bundle length. The experimental data are compatible with these fundamental theoretical findings, but further investigations are necessary to make the work conclusive concerning the validity of the inferences for filamentous actin structures in cells.

eLife assessment

The work is a fundamental contribution towards understanding the role of archaeal and plant D-aminoacyl-tRNA deacylase 2 (DTD2) in deacylation and detoxification of D-Tyr-tRNATyr modified by various aldehydes produced as metabolic byproducts in plants. It integrates convincing results from both in vitro and in vivo experiments to address the long-standing puzzle of why plants outperform bacteria in handling reactive aldehydes and suggests a new strategy for stress-tolerant crops. A limitation of the study is the lack of evidence for accumulation of toxic D-aminoacyl tRNAs and impairment of translation in plant cells lacking DTD2.

eLife assessment

This manuscript describes structures of HER4 homo- and HER4/HER2 hetero-dimer complexes using single particle cryo-EM. This important work describes convincingly new structural details of these complexes that expand our understanding of their function. This work will be of interest to researchers working on cell surface signalling and kinase activity.

eLife Assessment

In this potentially important study, the authors report results of QM/MM simulations and kinetic measurements for the phosphoryl-transfer step in adenylate kinase. The results point to the mechanistic proposal that the transition state ensemble is broader in the most efficient form of the enzyme (i.e., in the presence of Mg2+ in the active site) and thus a different activation entropy. With a broad set of computations and experimental analyses, the level of evidence is considered solid by some reviewers. On the other hand, there remain limitations in the computational analyses, especially regarding free energy profiles using different methodologies (shape of free energy profiles with DFTB vs. PBE QM/MM, and barriers with steered MD and umbrella sampling) and the activation entropy, leading some reviewers to the evaluation that the level of evidence is incomplete.

eLife assessment

The work by Hornberger and team presents a novel workflow for the visualisation of myofibrils with high resolution and contrast that will be highly valued by the scientific community. The methods include solid validation of both sample preparation and analysis, and have been used to make the fundamental discovery of myofibrillogenesis as the mechanism of mechanical loading-induced growth. Whether this mechanism is present in other settings of muscle growth (i.e., non-loading), other striated tissue (e.g myocardium), or is sex-dependent, will require future experiments.

eLife Assessment

This important study combines compelling experiments with optogenetic actuation and convincing theory to understand how signalling proteins control the switch between cell protrusion and retraction, two essential processes in single cell migration. The authors examine the importance of the basal concentration and recruitment dynamics of a guanine exchange factor (GEF) on the activity of the downstream effectors RhoA and Cdc42, which control retraction and protrusion. The experimental and theoretical evidence provides a model of RhoA's involvement in both protrusion and retraction and shows that these complex processes are highly dependent on the concentration and activity dynamics of the components.

eLife assessment

The work by Johnson and co-workers has identified an important role of 2-Hydroxybutyrate in skeletal muscle oxidative capacity in the early stages of exercise. Mechanistically, they show convincing data to support a role of 2-Hydroxybutyrate in the regulation of BCAA metabolism via SIRT4, ADP-Ribosylation, and CEBP. However, whether this is the sole mechanism and if these translate to longer exercise training regimes requires future experiments.

eLife assessment

The manuscript seeks to dissect the molecular underpinnings of poke and stretch activation in OSCA channels. While the structural and functional experiments are well done, and the authors present some important data, the reviewers identified weaknesses in experimental design and interpretation that render the data incomplete in supporting some of the main conclusions of the paper. Nevertheless, this work will be of interest to those working in the fields of mechanosensation, sensory biology, and ion channels.

eLife assessment

In this fundamental study, the authors analyzed associations between circulating immune cells and periodontitis. Convincing evidence identifies three immune cell types related to periodontitis, which substantially advances our understanding of periodontitis.

eLife assessment

This study presents a useful finding on the role of GABRD and its downstream target CDK1 in the progression of breast cancer. The evidence supporting the claims of the authors is somewhat incomplete and the elaboration of the mechanistic details on GABARD/CDK1 regulation would have strengthened the study. The work will be of interest to clinicians and biologists working on breast cancer.

eLife assessment

This fundamental study addresses the earliest events that enable plant roots to reorient growth in response to gravity. Compelling molecular and cell biological data establish that plasma membrane localization of the LAZY or NEGATIVE GRAVITROPIC RESPONSE OF ROOTS (NGR) protein family is required for rapid and polar redirection of D6 protein kinase, an activator of the PIN3 auxin transporter. This work complements and extends recent publications on the NGR family in gravity sensing (PMID: 37741279 and PMID: 37561884). Collectively these papers advance our understanding of rapid plant gravity sensing and response.

eLife assessment

This manuscript reports important in vitro biochemical and in planta experiments to study the receptor activation mechanism of plant membrane receptor kinase complexes with non-catalytic intracellular kinase domains. Several lines of evidence convincingly show that one such putative pseudokinase, the immune receptor EFR achieves an active conformation following phosphorylation by a co-receptor kinase, and then in turn activates the co-receptor kinase allosterically to enable it to phosphorylate down-stream signaling components. This manuscript will be of interest to scientists focusing on cell signalling and allosteric regulation.

eLife assessment

This valuable study examines whether the BMP signaling pathway has a role in H3.3K27M DMG tumors, regardless of the presence of ACRVR1 activating mutations. The authors provide solid evidence that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. Although this work could be further enhanced by the inclusion of additional models, the study overall points to BMP2/7 as a potential target for future therapies in this deadly cancer.

eLife assessment

This manuscript describes fundamental single-molecule correlative force and fluorescence microscopy experiments to visualize the 1D diffusion dynamics and long-range nucleosome sliding activity of the yeast chromatin remodelers, RSC and ISW2. Compelling evidence shows that both remodelers exhibit 1D diffusion on bare DNA but utilize different mechanisms, with RSC primarily hopping and ISW2 mainly sliding on DNA. These results will be of interest to researchers working on chromatin remodeling.

eLife assessment

This manuscript is a fundamental contribution to the understanding of the role of intrinsically disordered proteins in circadian clocks and the potential involvement of phase separation mechanisms. The authors convincingly report on the structural and biochemical aspects and the molecular interactions of the intrinsically disordered protein FRQ. The paper will be of interest to scientists focusing on circadian clock regulation, liquid-liquid phase separation, and phosphorylation.

eLife Assessment

This important study substantially advances our understanding of pediatric Crohn's disease, mapping the cellular make-up of this disease and how patients respond to treatment. The evidence supporting the conclusions is compelling, with thorough bioinformatic analyses, underpinned by rigorous methodology and data integration. The work will be of broad interest to pediatric clinicians, immunologists and bioinformaticians.